EGFR-targeted therapy results in dramatic early lung tumor regression accompanied by imaging response and immune infiltration in EGFR mutant transgenic mouse models

// Abhilash Venugopalan 1 , Min-Jung Lee 2 , Gang Niu 3 , Jose Medina-Echeverz 1 , Yusuke Tomita 2 , Martin J. Lizak 4 , Constance M. Cultraro 1 , Robert Mark Simpson 5 , Xiaoyuan Chen 3 , Jane B. Trepel 2 and Udayan Guha 1 1 Thoracic and Gastrointestinal Oncology Branch, National Cancer Institute, Bethesda, MD, USA 2 Developmental Therapeutics Branch, National Cancer Institute, Bethesda, MD, USA 3 Laboratory of Molecular Imaging and Nanomedicine, National Institute of Biomedical Imaging and Bioengineering, Bethesda, MD, USA 4 Mouse Imaging Facility, National Institute of Neurological Disorder and Stroke, National Institutes of Health, Bethesda, MD, USA 5 Laboratory of Cancer Biology and Genetics, National Cancer Institute, Bethesda, MD, USA Correspondence to: Udayan Guha, email: // Keywords : lung cancer, EGFR, TKI, imaging, immune-infiltration Received : May 23, 2016 Accepted : July 22, 2016 Published : August 02, 2016 Abstract Lung adenocarcinoma patients harboring kinase domain mutations in Epidermal growth factor receptor (EGFR) have significant clinical benefit from EGFR-targeted tyrosine kinase inhibitors (TKIs). Although a majority of patients experience clinical symptomatic benefit immediately, an objective response can only be demonstrated after 6-8 weeks of treatment. Evaluation of patient response by imaging shows that 30-40% of patients do not respond due to intrinsic resistance to these TKIs. We investigated immediate-early effects of EGFR-TKI treatment in mutant EGFR-driven transgenic mouse models by FDG-PET and MRI and correlated the effects on the tumor and the tumor microenvironment. Within 24 hours of erlotinib treatment we saw approximately 65% tumor regression in mice with TKI-sensitive EGFR L858R lung adenocarcinoma. However, mice with EGFR L858R/T790M -driven tumors did not respond to either erlotinib or afatinib monotherapy, but did show a significant tumor response to afatinib-cetuximab combination treatment. The imaging responses correlated with the inhibition of downstream EGFR signaling, increased apoptosis, and decreased proliferation in the tumor tissues. In EGFR L858R -driven tumors, we saw a significant increase in CD45 + leukocytes, NK cells, dendritic cells, macrophages and lymphocytes, particularly CD8 + T cells. In response to erlotinib, these dendritic cells and macrophages had significantly higher MHC class II expression, indicating increased antigen-presenting capabilities. Together, results of our study provide novel insight into the immediate-early therapeutic response to EGFR TKIs in vivo .